Journal Article

Histone deacetylase inhibitor suberoylanilide hydroxamic acid suppresses the pro-oncogenic effects induced by hepatitis B virus pre-S<sub>2</sub> mutant oncoprotein and represents a potential chemopreventive agent in high-risk chronic HBV patients

Yi-Hsuan Hsieh, Ih-Jen Su, Chia-Jui Yen, Ting-Fen Tsai, Hung-Wen Tsai, Han-Ni Tsai, Yu-Jun Huang, Yen-Yu Chen, Yu-Lin Ai, Lin-Yuan Kao, Wen-Chuan Hsieh, Han-Chieh Wu and Wenya Huang

in Carcinogenesis

Volume 34, issue 2, pages 475-485
Published in print February 2013 | ISSN: 0143-3334
Published online November 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs365
Histone deacetylase inhibitor suberoylanilide hydroxamic acid suppresses the pro-oncogenic effects induced by hepatitis B virus pre-S2 mutant oncoprotein and represents a potential chemopreventive agent in high-risk chronic HBV patients

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Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) in type II ground glass hepatocytes (GGHs) has been recognized as an emerging viral oncoprotein; it directly interacts with the c-Jun activation domain-binding protein 1 (JAB1) and subsequently causes hyperphosphorylation of the tumor-suppressor retinoblastoma and, consequently, leads to disturbed cell cycle progression. The interaction of the pre-S2 mutant LHBS with JAB1 could provide a potential target for chemoprevention. In this study, we found that the preneoplastic type II GGHs showed a significant decrease of the cyclin-dependent kinase inhibitor p27Kip1, which serves as a marker for pre-S2 mutant-JAB1 complex formation. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) elevated expression of the tumor-suppressor thioredoxin-binding protein 2 (TBP2), which subsequently enhanced the JAB1-TBP2 interaction and abolished the pre-S2 mutant LHBS-induced degradation of p27Kip1, which, in turn, recovered the normal cell cycle checkpoint. The pre-S2 mutant LHBS-induced pro-oncogenic effects: increased cell proliferation, nuclear/cytoplasmic ratio and proliferating cell nuclear antigen expression, were all greatly ameliorated after SAHA treatments, which suggested SAHA as a promising chemopreventive agent for the pre-S2 mutant oncoprotein-induced HCC. In conclusion, this study provides the mechanism of histone deacetylase (HDAC) inhibitor in preventing the pre-S2 mutant-induced oncogenic phenotype. The HDAC inhibitor SAHA is therefore a potential chemopreventive agent for high-risk chronic HBV patients who may develop HCC.

Journal Article.  7764 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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